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Benzene Metabolism by Ethanol-, Acetone-, and Benzene-inducible Cytochrome P-450 (IIE1) in Rat and Rabbit Liver Microsomes¹

Department of Physiological Chemistry, Karolinska Institute, P. O. Box 60400, S-10401 Stockholm, Sweden

Ethanol is known to exert a synergistic effect on the toxicity of benzene. In the present investigation it was found that benzene was metabolized at a rate 20-65-fold higher in liver microsomes from ethanol- or acetone-treated rats than in microsomes from control animals. One high affinity site [K_m = 19 ± 5 (SD) µM] and one low affinity site [K_m = 0.3 ± 0.1 mM] for benzene metabolism were present in microsomes of acetone-treated rats, and similar sites were seen in microsomes from control or ethanol-treated rats. Treatment of the animals with either ethanol or acetone mainly influenced the V_max values for benzene metabolism. Also benzene treatment of rats caused an increased rate of microsomal benzene metabolism. The hepatic microsomal NADPH-dependent metabolism of benzene was inhibited by compounds known to interact with the ethanol-inducible form of P-450 such as imidazole, ethanol, aniline, and acetone but was unaffected by addition of metyrapone. Anti-IgG against ethanol-inducible cytochrome P-450 from rat (P-450j) or rabbit liver (P-450 LMeb) inhibited the microsomal benzene metabolism effectively in rat or rabbit liver microsomes, respectively, whereas preimmune IgG was without effect. The level of rat ethanol-inducible P-450 (P-450j) was induced to an extent similar to that for the microsomal benzene metabolism, by either benzene, acetone, or ethanol. The data indicate that benzene is metabolized mainly by the ethanol-inducible P-450 form in liver microsomes and that the induction of this isozyme by ethanol can provide an explanation for the synergistic action of ethanol on benzene toxicity.

¹ Supported by grants from Magn. Bergvalls Stiftelse and from the Swedish Medical Research Council.

² To whom requests for reprints should be addressed.

Received 7/23/87. Revised 6/15/88. Accepted 6/21/88.

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